Healthy Volunteers (Intended Indication: Chronic Kidney Disease) Clinical Trial
Official title:
A Single-Centre, Randomised, Double-Blind, Placebo-Controlled, 3-Period, Cross-Over Phase I Study to Investigate the Effect on the QTcF Interval of a Single Dose of 2 Different Doses of Verinurad, Each in Combination With Allopurinol 300 mg, Compared With Placebo In Healthy Volunteers
| Verified date | November 2021 |
| Source | AstraZeneca |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This study will be conducted to investigate the safety of verinurad in healthy volunteers in combination with allopurinol 300 mg, compared with placebo in particular its effect on electrocardiogram (ECG), with focus on the QT/QTc interval
| Status | Completed |
| Enrollment | 24 |
| Est. completion date | August 21, 2020 |
| Est. primary completion date | August 21, 2020 |
| Accepts healthy volunteers | Accepts Healthy Volunteers |
| Gender | All |
| Age group | 18 Years to 50 Years |
| Eligibility | Inclusion Criteria: 1. Provision of signed and dated, written informed consent prior to any study-specific procedures. 2. Healthy male and female subjects aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venipuncture. 3. Females must have a negative pregnancy test at Screening and on admission to the study centre must be: (1) Not pregnant or currently lactating or breast-feeding. (2) Of non-childbearing potential confirmed at the Screening Visit by fulfilling one of the following criteria: (i) Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range (FSH >40 IU/mL). (ii) Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. (3) OR, if of childbearing potential, must be willing to use an acceptable method of contraception to avoid pregnancy for the entire study period and 3 months after the Follow-up Visit. 4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive. 5. Serum uric acid (sUA) <300 µmol/L at Screening (Visit 1) and sUA <330 µmol/L on Day -1 in every treatment period (Visit 2 to 4). Note: Since sUA levels might vary on a daily basis, subjects with sUA =330 µmol/L on Day -1 will be retested. Treatment on Day 1 will only be administered when the sUA level on Day -1 is <330 µmol/L upon retesting. Subjects with sUA =330 µmol/L despite retesting, may conduct the treatment period at a later date when they have sUA <330 µmol/L. 6. Must be able to swallow multiple capsules/tablets. Exclusion criteria: 1. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. 2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. 3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of investigational medicinal product (IMP). 4. Subject has a positive test result for SARS-CoV-2 RT-PCR before randomisation. 5. Subject has clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission. 6. History of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated). 7. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results, at Screening (Visit 1) as judged by the Investigator, including: (1) Alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) (2) Aspartate aminotransferase (AST) >1.5 × ULN (3) Bilirubin (total) >1.5 × ULN (4) Gamma glutamyl transpeptidase (GGT) >1.5 × ULN 8. Any clinically significant abnormal findings in vital signs at Screening as judged by the Investigator, including: (1) Systolic blood pressure <90 mmHg or >140 mmHg (2) Diastolic blood pressure <50 mmHg or >90 mmHg (3) Heart rate <50 or >90 bpm 9. Carrier of the HLA-B*58:01 allele. 10. Any clinically important abnormalities in rhythm, conduction or morphology of the 12 lead safety ECG and any clinically important abnormalities in the 12-lead safety ECG as considered by the Investigator that may interfere with the interpretation of QT interval corrected for heart rate using Fridericia's formula (QTcF), including abnormal ST T wave morphology, particularly in the Clinical Study Protocol (CSP)-defined primary lead for dECG analysis or left ventricular hypertrophy: 1. Prolonged QTcF >450 ms or shortened QTcF <340 ms or family history of long QT syndrome. 2. PR (PQ) interval shortening <120 ms (PR >110 ms but <120 ms is acceptable if there is no evidence of ventricular pre-excitation). 3. PR (PQ) interval prolongation (>220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation. 4. Persistent or intermittent complete bundle branch block, incomplete bundle branch block, or intraventricular conduction delay with QRS >110 ms. Subjects with QRS >110 ms but <115 ms are acceptable if there is no evidence of ventricular hypertrophy or pre-excitation. 11. Any positive result on Screening for serum hepatitis B surface antigen OR anti-HBc antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody. 12. Suspected or known Gilbert's syndrome. 13. Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to Screening. 14. Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by the Investigator. Excessive intake of alcohol defined as the regular consumption of more than 24 g of alcohol per day for men or 12 g per day for women. 15. Positive screen for drugs of abuse, cotinine (nicotine) or alcohol at the Screening Visit or on each admission to the study centre. 16. Excessive intake of caffeine-containing drinks or food (eg, coffee, tea, chocolate) as judged by the Investigator. Excessive intake of caffeine defined as the regular consumption of more than 600 mg of caffeine per day (eg, >5 cups of coffee) or would likely be unable to refrain from the use of caffeine-containing beverages during confinement at the study site. 17. Previous hypersensitivity reaction to allopurinol or any URAT1 inhibitor. 18. Subjects who are pregnant, breast-feeding or planning to become pregnant (pregnancy is to be avoided for the entire study period and 3 months after the Follow up Visit). 19. Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. 20. Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 × the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or within 5 half-lives (whichever is longer). Hormone replacement therapy is allowed for females. 21. Plasma donation within 1 month of Screening or any blood donation/blood loss >500 mL during the 3 months prior to Screening. 22. Has received another new chemical or biological entity (defined as a compound which has not been approved for marketing in the US) within 30 days or within 5 half lives (whichever is longer) of the first administration of IMP in this study. Note: Subjects consented and screened, but not randomised in this study or a previous Phase I study, are not excluded. 23. Involvement of any AstraZeneca, Parexel or study site employee or their close relatives. 24. Subjects who have previously received verinurad. 25. Subjects who cannot communicate reliably with the Investigator and/or are not able to read, speak and understand the German language. 26. Judgment by the Investigator that the subject should not participate in the study if there are any ongoing or recent (ie, during the Screening Period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with study procedures, restrictions and requirements. 27. Subjects who are vegans or have medical dietary restrictions. 28. Vulnerable subjects, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 29. Subjects who are regularly exposed to COVID-19 (eg, health care professionals working in COVID-19 wards or at emergency departments) as part of their daily life. |
| Country | Name | City | State |
|---|---|---|---|
| Germany | Research Site | Berlin |
| Lead Sponsor | Collaborator |
|---|---|
| AstraZeneca | Parexel |
Germany,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Model Predicted Baseline-corrected and Placebo-corrected QT Interval Corrected for Heart Rate (HR) Using Fridericia's Formula (QTcF)(??QTcF) (Derived From Concentration-QTcF Analysis) at Geometric Mean of Cmax of Verinurad | Assessment of the effect of a single dose of verinurad given as either a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of International Council for Harmonisation Guideline E14 and associated Questions and Answers [ICH E14 Q&A]), both in combination with allopurinol 300 mg, on the QTcF interval compared to placebo using a concentration-QTcF analysis. A linear mixed-effect concentration-QTcF model was used as the primary analysis. This is a result of the statistical model so it does not have values for every timepoint, it is just one set of numbers - summarizes data across all timepoints. No non-placebo-corrected QTcF data values were collected or could be obtained for each Arm/Group at Cmax of Verinurad. |
Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected Heart Rate (?HR) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on heart rate (HR). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hour (h) post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-adjusted Heart Rate (??HR) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on HR. | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected RR Interval (?RR Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (RR). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-adjusted RR Interval (??RR Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (RR). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected PR Interval (?PR Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (PR). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-adjusted PR Interval (??PR Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (PR). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected QRS Interval (?QRS Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QRS). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-corrected QRS Interval (??QRS Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QRS). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected QT Interval (?QT Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QT). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-corrected QT Interval (??QT Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QT). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected QTcF Interval (?QTcF Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QTcF). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Baseline-corrected and Placebo-corrected QTcF Interval (??QTcF Interval) | Investigation of the effect of verinurad given either as a 24 mg ER8 formulation (clinical exposure) or a 40 mg IR formulation (exposure needed to waive positive control as per question 5.1 of ICH E14 Q&A), both in combination with allopurinol 300 mg, on additional dECG variable (QTcF). | Baseline; Day 1: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 h post-dose; Day 2: 24 and 36 h post-dose; Day 3: 48 h post-dose | |
| Secondary | Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the pharmacokinetic (PK) of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC[0-t]) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Maximum Observed Plasma Concentration (Cmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Time to Reach Maximum Plasma Concentration (Tmax) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Time Delay Between Drug Administration and the First Observed Concentration in Plasma (Tlag) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Terminal Half-life (t½?z) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Time of Last Quantifiable Plasma Concentration (Tlast) for Verinurad, M1, M8, Allopurinol, and Oxypurinol | Assessment of the PK of verinurad and its metabolites (M1 and M8) and allopurinol and its metabolite (oxypurinol) in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Apparent Total Body Clearance of Drug From Plasma After Extravascular Administration (Parent Drug Only) (CL/F) for Verinurad and Allopurinol | Assessment of the PK of verinurad and allopurinol in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Parent Drug Only) (Vz/F) for Verinurad and Allopurinol | Assessment of the PK of verinurad and allopurinol in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Apparent Volume of Distribution at Steady State Following Extravascular Administration (Parent Drug Only) (Vss/F) for Verinurad and Allopurinol | Assessment of the PK of verinurad and allopurinol in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity (MRT) for Verinurad and Oxypurinol | Assessment of the PK of verinurad and allopurinol in healthy participants. | Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 hours post-dose; Day 2: 24 and 36 hours post-dose; Day 3: 48 hours post-dose | |
| Secondary | Number of Participants With Adverse Events (AEs) | Examination of the safety and tolerability of verinurad and allopurinol. | From Screening (Day -28 to Day -2) until the Follow-up visit (7 to 10 Days After the Last Dose) |